Fixation of the two Tabun isomers in acetylcholinesterase: a QM/MM study

Dysfunction of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat since AChE is a key enzyme in neurotransmission. To more rigorously design reactivation agents, it is of prime importance to understand the mechanism of inhibition of AChE by OP compounds. Tabun is one of the more potent nerve agents. It is produced as a mixture of two enantiomers, one of them (the levorotatory isomer) being 6.3 times more potent. Could it be that the inhibition mechanism is different for the two enantiomers? To address this critical issue, we used a hybrid quantum mechanics/molecular mechanics (QM/MM) methodology. Calculations were performed using BP86 functional and TZVP basis set. Single points were also done with B3LYP and PBE0 functionals. We studied the four possible attacks of tabun on the oxygen of Ser203 using two crystallographic structures (PDB codes 2C0P and 3DL7): (S) tabun with the cyano group syn to the oxygen of Ser203 and (R) tabun with the cyano group anti, corresponding to the experimental X-ray structure; (S) tabun with the cyano group anti to the oxygen of Ser203 and (R) tabun with the cyano group syn, leading to a different isomer than was experimentally seen. We found that the most active enantiomer is (S) tabun with the cyano group syn to the oxygen of Ser203. Thus it seems that the cyano group does not leave anti to the oxygen of Ser203 due to repulsive polar interactions between cyanide and aromatic residues in the active site.